Hepatic Activation

What is Hepatic Activation?

The theory behind the procedure is that diabetes is a complex metabolic process gone awry. Traditional diabetes therapy attempts to normalize blood sugar levels without considering the complexity of the problem. The simple strategy of most therapy is, "Give insulin when glucose is high and don't give insulin when glucose is low or normal." In contrast, Hepatic Activation attempts to reestablish the normal biochemical and physiological relationships between the gastrointestinal tract, liver and muscle.

Hepatic Activation is a special method of intravenous insulin infusion to treat diabetes. The program is designed to biochemically and physiologically "reawaken" the liver so that it will return to its important role of auto-regulating the blood sugar level.

The method uses intravenous infusions of large amounts of insulin to "awaken" or activate the liver's production of certain enzymes. The enzymes enable glucose to be "burned" in the liver to produce energy, stored as liver glycogen for later use, or converted into fat or protein.

Why is Hepatic Activation needed?

The liver requires large amounts of insulin and glucose arriving at the same time in order to stimulate the production of liver enzymes, such as glucokinase, which "tags" glucose with a phosphate group, a process necessary for "burning" or storing glucose. Normally,  insulin comes directly to the liver from the pancreas through the portal vein. The insulin coming into the liver after a large meal may be 50 to 100 times the levels seen in other parts of the body.

These high insulin levels then activate glucokinase and other enzymes needed to process the glucose that is also coming in. The activated enzymes, in turn, let the liver remove about half the glucose digested in a meal and keep postmeal blood sugars from spiking. When these enzymes remain inactive because the liver is no longer exposed to the large postmeal release of insulin directly from the pancreas (i.e. type I diabetes mellitus), blood sugars begin to spike after meals, making control difficult.

When a person with diabetes injects insulin subcutaneously, the concentration of insulin at the liver is never great enough to trigger the liver to produce these enzymes. So the injected insulin lowers the blood sugar, which is necessary for life, but doesn't do as good a job of stabilizing control to avoid the complications of diabetes.

Who developed this research?

The principal researcher responsible for developing the Hepatic Activation process is Dr. Thomas Aoki, Professor of Medicine and Chief, Division of Endocrinology, University of California, Davis. Dr. Aoki is a former Head of the Metabolism Section at the Joslin Diabetes Center in Boston and a former faculty member at Harvard Medical School. He has worked on this approach for almost 25 years.

What's involved in Hepatic Activation for the person receiving it?

A person receiving Hepatic Activation typically spends 8 hours a week in a clinic with a specially designed pump infusing insulin directly into the blood stream through a vein in the forearm. The pump infuses insulin pulses of the proper dosage and timing to signal the liver to make the missing enzymes. Total doses of between 20 and 100 units are typically required for a full day's treatment for a 70 kg person. The blood sugar is checked every 15 to 30 minutes, and glucose is drunk or carbohydrate is eaten to balance the effect of insulin. This infusion is performed for an hour, then discontinued for 60-90 minutes with alternating periods for the 8 hour time span. During the time the infusion is discontinued, the person can be up and walking around. During the treatment, the patient occasionally breathes into a machine to measure the respiratory quotient, the ratio of oxygen consumed to carbon dioxide produced, to monitor the restoration process going on in the liver.

The person also receives training in how to control their blood sugars with diet, exercise, multiple injections of insulin, and blood sugar testing during the rest of the week. Unless they follow this plan, the benefits of Hepatic Activation are not fully realized. To receive ongoing benefits, this regimen of Hepatic Activation must continue for the rest of the patient's life.

Soon there may be an easier way.

A more convenient way to receive the treatment may someday be available. An ongoing clinical trial is testing the ability of select patients to perform this infusion therapy at home for an 8 hour period weekly for 5 weeks. The 6th week the patient returns to the clinic for the insulin infusion and tests. These patients are allowed to do this only after they have received the infusion in the clinic for at least 6 months so that they are fully trained and their response to the treatment has been observed. They are also required to have a partner trained in the procedure who would be available to assist them if they experience low blood sugars during the treatment. The results of this trial have been favorable and may be available in the future for patients at clinical sites.

Who can benefit from Hepatic Activation?

Hepatic Activation may stabilize advanced kidney or heart disease related to diabetes, progressive retinal disease, debilitating orthostatic hypotension, and chronic foot ulcers.

One example of improvement is a 47 year old woman with diabetes who had a dangerously enlarged heart and was awaiting a heart transplant. After starting Hepatic Activation, she recovered enough cardiac function to be removed from the transplant list. 4 1/2 years later, she walks 3 to 4 miles a day, and cardiovascular tests document a 30 to 40 percent improvement in cardiac function.

No studies have been done to specifically show how Hepatic Activation benefits these organ systems or why patients' activity levels increase, but Dr. Aoki speculates that increased glucose utilization by muscle (cardiac and skeletal) may be the explanation.

However, another benefit of Hepatic Activation has shown documented results. A study of 20 "brittle" diabetic patients over 42 months showed that Hepatic Activation resulted in a 98 percent decrease in major hypoglycemic reactions. Patients became aware of drops in their blood sugar levels whereas before they had had hypoglycemic unawareness. They went from an average of three hypoglycemic episodes a month to an average of 0.1 during the same time period. The frequency returned to three a month when Hepatic Activation was stopped.

A nine month clinical trial conducted at several research centers (Joslin Diabetes Center, Scripps Institute, Mayo Clinic, Temple University, University of Maryland, and University of Arizona), recently demonstrated the ability of Hepatic Activation to slow progression of diabetic nephropathy (kidney disease)  in 70 acutely ill patients. Patients in the control group had an 8.15 ml/min/yr rate of decline in creatinine clearance during the study period. The treatment group preserved kidney function, only experiencing a decline of only 0.89 ml/min/yr. These results were independent of differentially improved glucose control or blood pressure control and independent of differences in office attendance between groups.

Where is Hepatic Activation available?

The University of California Davis School of Medicine and Medical Center is currently the only academic medical center in the nation offering Hepatic Activation to patients as a fee-for-service outpatient treatment. Other sites located in Santa Rosa Ca, Denver CO, Wichita KS, Midland TX, and soon in West Dartmouth MA, have been offering the treatment for over the past four years. Some insurance policies cover the cost of Hepatic Activation.


Not everyone is convinced of Dr. Aoki's results. He says in the April, 1996 issue of MATRIX, a UC Davis Medical Center publication, "I've had difficulty getting my work published by several of the major medical journals. In fact, the editor of one of these journals confided that the reviewers don't believe the data." The European journal Lancet published his results in 1993, and he has published seven other papers regarding Hepatic Activation in U.S. journals.

Are there alternatives?

Hypoglycemia unawareness can also be stopped by other methods, several of which are simpler or more convenient (see STOP the Rollercoaster ). However, these other methods have not been proven to have any stabilizing effects on diabetes complications.

There are also some alternatives to Hepatic Activation to increase insulin delivery to the liver. One is the placement of encapsulated beta cells into the abdominal cavity. Another solution uses an insulin pump surgically implanted under the skin with a catheter that delivers insulin into the abdominal cavity. This methods have been tested extensively and found to greatly stabilize blood sugars. However, federal funding for the internal pump program dried up due to frequent clogging of the catheter, loss of insulin delivery and an excess risk of infection.

Another more interesting solution, currently used in Europe, is to place a port directly from the abdominal wall into the peritoneal cavity in the abdomen. Then an external insulin pump delivers insulin through the port on the outside of the abdomen directly into the peritoneal cavity. Although an external pump is needed, only minor surgery is required, risks of infection are low with current ports, and overall costs are reduced compared to Hepatic Activation or an internal pump. However, again, this alternative has not been proven to stabilize the complications of diabetes, although prospects appear to be good.

All these methods increase insulin delivery to the liver and at the same time decrease peripheral levels to more normal values. Research comparing all of these methods to each other has never been done, so the information necessary to finding the best method is not available at this time.